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Harnessing Targeted Nanotheranostics to Reprogram Activated Leukocytes in Inflammatory Bowel Disease

Periodic Reporting for period 3 - LeukoTheranostics (Harnessing Targeted Nanotheranostics to Reprogram Activated Leukocytes in Inflammatory Bowel Disease)

Reporting period: 2018-11-01 to 2020-04-30

Inflammatory bowel diseases (IBD) comprises a group of chronic inflammations of the gastro-intestinal tract. The two main types are Crohn's Disease and Ulcerative Colitis. While IBD has been extensively studied in the past decades and especially recently since emerging technologies enabled DNA sequencing of intestinal bacteria, the development of new treatments have been progressing slowly. Only since recently, some more specific therapies like antibodies against α4β7 integrin and TNF-α are being used. Because of the complexity of intestinal immunity, we believe that a tailor-made therapy is required. We are working on a project that targets lipid nanoparticles (LNPs) specifically to immune cells actively participating in the intestinal inflammation. We do this by coating the LNPs with a protein that contains part of MAdCAM-1, the natural ligand of α4β7 integrin. This ligand recognizes only the high-affinity conformation of α4β7 integrin, a conformation that enables immune cells to migrate to the gut. Using this system, we want to deliver therapeutic siRNA specifically to these cells while leaving other cells untouched.
The incidence of IBD in Europe is rising and with it, its associated healthcare costs (~ 5 billion euro/year in 2013). Novel therapeutics like Humera and Entyvio are promising drugs but leave patients dependent on expensive monoclonal antibodies for a long period. We envision manipulating pro-inflammatory immune cells by silencing specific target genes and thereby we strive to restore the natural immunological balance.
The main objective of this project is to deliver siRNA against a pro-inflammatory target (e.g. IFN-γ or TNF-α) in vivo in a colitis mouse model and achieve therapeutic efficacy. Furthermore, we are developing more accurate diagnostic tools by labeling the activated immune cells with Cu64 to analyze the disease with PET/CT.
So far, the main results include the design, production and purification of a recombinant protein containing essential binding domains to α4β7 integrin and a domain that allows for efficient conjugation to the LNPs. We characterized and optimized the binding to immune cells in vitro and achieved in vivo gene silencing of a reporter gene in experimental colitis model.
We are currently investigating the therapeutic potential of this approach by silencing therapeutically relevant genes in either DSS-induced colitis in wild type (WT) mice or Piroxicam-induced colitis in IL-10 knockout (KO) mice.